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Induction of Murine Intestinal Inflammation by Adoptive Transfer of Effector CD4+CD45RBhigh T Cells into Immunodeficient Mice
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TNFR2 activates MLCK-dependent tight junction dysregulation to cause apoptosis-mediated barrier loss and experimental

Liping Su1, Sam C Nalle, Le Shen

  • 1Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Gastroenterology
|April 27, 2013
PubMed
Abstract

Insights

Tumor necrosis factor receptor 2 (TNFR2) signaling promotes inflammatory bowel disease by increasing myosin light chain kinase (MLCK) expression, leading to barrier loss. Advanced stages involve apoptosis-independent of MLCK.

Area of Science:

  • Gastroenterology
  • Immunology
  • Cell Biology

Background:

  • Inflammatory bowel disease (IBD) involves gut barrier dysfunction due to tight junction issues and epithelial damage.
  • The precise mechanisms regulating these processes and their roles in IBD pathogenesis require further elucidation.

Purpose of the Study:

  • Investigate the roles of tumor necrosis factor receptor (TNFR) 1, TNFR2, and myosin light chain kinase (MLCK) in regulating intestinal barrier function during colitis.
  • Determine the distinct mechanisms of barrier loss in immune-mediated versus damage-induced colitis models.

Main Methods:

  • Utilized mouse models of colitis, including CD4(+)CD45RB(hi) adoptive transfer and dextran sulfate sodium administration.
  • Examined mice deficient in TNFR1, TNFR2, or long MLCK.
  • Analyzed intestinal tissues and epithelial cells using immunoblotting, immunofluorescence, ELISA, and real-time PCR.

Main Results:

  • Immune-mediated colitis increased intestinal permeability, claudin-2 expression, long MLCK, and TNFR2 signaling, alongside myosin II light chain phosphorylation.
  • TNFR2 deficiency attenuated barrier loss and weight loss in adoptive transfer models.
  • Long MLCK deficiency delayed colitis onset but did not prevent disease progression via apoptosis.

Conclusions:

  • TNFR2 signaling drives barrier loss in immune-mediated colitis through increased long MLCK expression.
  • Advanced colitis involves MLCK-independent barrier loss via apoptosis and mucosal damage.
  • Distinct mechanisms of barrier loss offer potential therapeutic targets for inflammatory bowel disease.
Keywords:
CA-MLCKDSSDisease ProgressionEpithelial BarrierIBDInflammatory Bowel DiseaseIntestinal PermeabilityMLCMLCKRag1TNFTNFRconstitutively active myosin light chain kinasedextran sulfate sodiuminflammatory bowel diseasemyosin II regulatory light chainmyosin light chain kinaserecombinase activating gene 1tumor necrosis factortumor necrosis factor receptor

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